The efficiency of cancer chemotherapy protocols tends progressively to decrease in inverse proportion to the target tumor's progressive increase in drug resistance. Accordingly, early detection of drug resistance would significantly benefit the development, choice and timing of alternative treatment strategies. Currently, the multidrug resistant (MDR) gene offers a potential for monitoring tumor resistance to some natural agents such as the vinca alkaloids, Vincristine and Vinblastine; antibiotics such as Daunorubicin, Actinomycin D, Doxorubicin, Mitomycin C, Etoposide (VP-16), Teniposide (VM-26) and Mithramycin.
Amplification of genes associated with drug resistance has been monitored by a modified polymerase chain reaction (PCR) assay, as described in Kashani-Sabet, et al., "Detection of Drug Resistance in Human Tumors by in Vitro Enzymatic Amplification," Cancer Res. 48:5775-5778 (1988). Acquired drug resistance has been monitored by the detection of cytogenetic abnormalities, such as homogeneous chromosome staining regions and double minute chromosomes.
Several shortcomings attend these procedures. Gene amplification techniques other than PCR are applicable only to DNA, require at least 10.sup.6 tumor cells and cannot discriminate less than two to four fold changes, whereas drug resistant tumors may be indicated by lower gene amplification levels. Drug resistance has been manifested by tumors in the absence of gene amplification or cytogenetic abnormalities. The detection of tumor progression by imaging lacks reliability and precision.
No efficient, generally applicable non-invasive procedure for the early detection of or for monitoring the changes in drug resistance over time is presently known.